EP1166787A2 - Solutions stables pour la dialyse péritonéale et la hémodialyse conténant du bicarbonate et des acides aminés - Google Patents

Solutions stables pour la dialyse péritonéale et la hémodialyse conténant du bicarbonate et des acides aminés Download PDF

Info

Publication number
EP1166787A2
EP1166787A2 EP01600017A EP01600017A EP1166787A2 EP 1166787 A2 EP1166787 A2 EP 1166787A2 EP 01600017 A EP01600017 A EP 01600017A EP 01600017 A EP01600017 A EP 01600017A EP 1166787 A2 EP1166787 A2 EP 1166787A2
Authority
EP
European Patent Office
Prior art keywords
solution
bicarbonate
amino acids
solutions
acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01600017A
Other languages
German (de)
English (en)
Other versions
EP1166787A3 (fr
Inventor
Hippocrates Yatzidis
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of EP1166787A2 publication Critical patent/EP1166787A2/fr
Publication of EP1166787A3 publication Critical patent/EP1166787A3/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/424—Oxazoles condensed with heterocyclic ring systems, e.g. clavulanic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides

Definitions

  • PD Peritoneal dialysis
  • HD hemodialysis
  • Such solutions should have an electrolyte formula resembling as closely as possible that of normal plasma and contain, for example, sodium, potassium, chloride, calcium and magnesium ions.
  • glucose is used as an osmotic agent while lactate, acetate and bicarbonate ions as buffering agents. All currently used PD solutions still have many drawbacks with serious consequences, arizing mainly from lactate, the low pH (5.2) and the high glucose concentrations and in HD solution from acetate.
  • peritoneal solutions must be sterilized by autoclaving at a pH around 5.2 in order to avoid the carmelisation, toxic substances are generated such as glucose byproducts (5 hydroxyl methyl furfurol, furandic carboxylic acid, acetyl acrylic acid), advanced glycosylation end byproducts (AGEs), and reactive oxygen species (ROS) which damage peritoneum and its function.
  • glucose byproducts (5 hydroxyl methyl furfurol, furandic carboxylic acid, acetyl acrylic acid), advanced glycosylation end byproducts (AGEs), and reactive oxygen species (ROS) which damage peritoneum and its function.
  • ROS reactive oxygen species
  • acetate in HD solution (dialysate) is unable to control metabolic acidosis and furtermore has the potential of causing bicarbonate deficit, accumulation of acetate and its metabolites, as well as for consequent acid-base and hemodynamic disturbances.
  • Bicarbonate has many advantages as it is the major natural buffer, with the better interdialytic hemodynamic stability and tolerance, can restore effectively acidosis with beneficial effects on protein metabolism, nutrition, the skeleton and the overall well-being of patients.
  • bicarbonate could react with calcium and magnesium and form insoluble neutral calcium and magnesium carbonate salts.
  • the on-line technique produces a non authentic bicarbonate solution as it becomes unstable during infusion and may decrease bicarbonate and favor the accumulation in the patient's plasma of carbonic acid, carbon dioxide, soluble hydrogen calcium and magnesium carbonates and finally insoluble neutral calcium and magnesium carbonate, the deposition of which, become evident on the wall of the connecting tubes (1-6).
  • disodium hydrogen citrate at a very low concentration (1.5 mM/L) into the PD and HD solutions of a pH 7.25 -7.45, completely abolishes the well known reaction between bicarbonate and calcium-magnesium.
  • disodium hydrogen citrate because may control the indicated pH and also because it is more stable than trisodium citrate. Amino acids added in PD solution instead of glucose.
  • Amino acids are the structural units from which proteins are synthesized. They are unevenly distributed in the media of the body and are chemically reactive. Because amino acids possess a basic amino group they have the power to combine with either alkali or acid, acting as buffers. Amino acids can be classified, according to their chemical structures and reaction into 3 groups, in basic amino acids in which the ratio between basic amino group and acid carboxyl group is 2:1, in neutral amino acids in which the ratio is 1:1 and in acidic amino acids in which this ratio is 1:2. Dietary amino acids are a good source of energy in some organs. Thus almost 50% of oxygen consumed by the liver is used for amino acid oxidation, and in small intestine is almost 30%. In the muscle and kidney, however these figures are 7.5% and 12.5%, respectively.
  • amino acids used are different, one to another in respect of quantitative and qualitative structure. In fact, it contains at relatively high concentration ten indispensable amino acids, histidine, leucine, lysine ⁇ HCl, methionine, phenylalamine, threonine, tryptophan, valine, arginine, and glutamine.
  • the total amount of amino acids in our solution is approximately 13.322 g/L and its their average mw is about 154.42 with a constant pH 7.25 to 7.45 during its storage and treatment.
  • Glycine, serine, proline, tyrosine, citrulline, ornitine, alanine, aspartic acid, glutamic acid and others dispensable amino acids were rejected from our single bicarbonate PD solution.
  • the nutritional property of these amino acids is rather poor while they dont have proved specific beneficial properties, except for an interesting cytoprotective action of glycine (6) and the antioxidant property of aspartic and glutamic acids (12).
  • serine is not safe, causing rats to die with anorexia, albuminuria, circulatory failure, congestion of liver and lungs (21). It is also doubtful if most of the above amino acids could form glycogen in excess and have an antiketogenic effect.
  • the ten amino acids included in our single bicarbonate PD solution are all indispensable which means that they cannot be synthesized in the human organism. Consequently, they may play a potent nutritional role by maintaining energy balance and thus combat and control the malnutrition of chronically uremic patients.
  • Kopple and Swendseid (24,25) established that histidine might be indispensable in chronically uremic patients, while others confirmed its indispensability (26,27).
  • Newer metabolic studies suggest that histidine at high concentration, is associated with anorexia in animals, which could lead to protein-energy malnutrition. Histidine, the biosynthetic precursor of the neurotransmiter histamine was found in these animals to be elevated in plasma and brain five times above normal.
  • protein-energy malnutrition consistently produces symptoms of depressed food intake, edema, growth failure and psychomotor changes (28), and it must be avoided.
  • histidine enhances nutrition, controls lipid metabolism (26) and maintains hemoglobin levels (29).
  • Leucine, lysine, methionine, threonine and valine are all well known indispensable amino acids. They are also the basic potent nutrients various studies showed that the concentrations of these amino acids could be increased manyfold without apparent toxic effects (30-34).
  • Phenylalanine and tryptophan are indispensable amino acids. Tryptophan is distinguished from other amino acids by its indole ring and it is the first of the amino acids to have been proved indispensable. Both are potent nutrients. They must be used at low concentrations, up to 2-3 mM/L, as they may cause transient brain disturbances in higher concentrations (35-37).
  • Arginine is the precursor of nitric oxide (NO) (38,39). Its supplementation in the hypercholesterolemic rabbits improves endothelium -dependent vasorelaxation, and shows that this improvement is associated with a reduction in atherogenesis (40-45). Also, in hypercholesterolemic patients arginine corrects the endothelial dysfunction in the vessels of microcirculation (46-49). Of great importance is also the effect of arginine in renal ischaemia. Schamm et al (50) demonstrated that arginine infusion was beneficial after 40 min clamping of the renal arteries, suggesting a regulatory role for the NO pathway in ischemic acute renal failure (ARF).
  • NO nitric oxide
  • arginine is the exclusive percursor of NO, a substance with a half-life of only a few seconds, and of a biological activity of 1-2 min. This activity ranges from disposal of protein metabolic waste, muscle metabolism, vascular tone regulation, immune system function, RNA synthesis, and on the release of numerous hormones (catecholamines, glucocorticoids, glucagon, growth hormone, insulin, prolactin, somatostatins), using different pathways, the disturbunce of which may produce detrimental effects.
  • arginine Dietary intervention with arginine may imrpove certain pathological states, such as diabetic nephropathy, cyclosporin A toxicity, salt-sensitive hypertention, ureteral obstruction, kidney hypertrophy due to high-protein feeding, and glomerular thrombosis due to administration of lipopolysachacharides (38,39,53).
  • pathological states such as diabetic nephropathy, cyclosporin A toxicity, salt-sensitive hypertention, ureteral obstruction, kidney hypertrophy due to high-protein feeding, and glomerular thrombosis due to administration of lipopolysachacharides (38,39,53).
  • Glutamine is the most abundant free amino acid in plasma and in intracellular pools in all tissues. In humans, glutamine accounts for approximately 20% of all amino acids. Glutamine for many years was neglected but now merits our attention, because during the last decade it was the topic of authentic skilful researchs by using isotopic techniques in human providing important and useful information. Today glutamine to be reported as the most important indispensable amino acid (54-57). A brief relation of their properties is needed.
  • Glutamine is the precursor of proteins and nucleotides; it is the substrate and the stimulator of glucogen and gluconeogenesis in all organs and tissues, while alanine gluconeogenesis is poor and takes place in liver only; it is also the regulator of carboxydrate metabolism and antiketoic; the stimulator for the formation of lipids; glutamine suppresses the proteolysis in liver and in skeletic muscles, stimulats their proteins synthesis and it is a strong nutrient (58-71). Finally, glutamine, as also aspartic acid and glutamic acid, according our studies, is a potent scavenger of ROS (see page 13).
  • Dissodium hydrogen citrate concentration is trivial and after its entry in circulation, citrate is rapidly metabolized to bicarbonate (72), while, the released calcium and magnesium regain their pure forms.
  • the consumption of disodium hydrogen citrate is trivial (0.708 g) for a 6-hr echange without any alteration of blood coagulation.
  • Preparation of both PD and HD solutions was carried out by dissolving chemicals in freshly produced ultrapure water taken by a procedure combining carbon perfusion, reverse osmosis and membrane filtration for retaining bacterials.
  • For preparation of HD solution a hundredfold dry mixture of all needed chemicals (984.5 g, see Table 2) was packed and stored in an air tight plastic bottle at room temperature. Thus may serve for preparing adequate dialysate for a routine HD session, by dissolving its content at 100 liters of freshly ultrapure water made by hand or mechanically.
  • PD solution could be sterilized by filtration, and also it can be sterilized by autoclaving, according the classical method used for sterilization of pure bicarbonate solution i.e. at 100°C for one hour, included in air tight plastic bag.
  • Sterilized PD solution protected from light and stored at temperature varying from 10 to 35°C, remained stable for at least six months. No precipitate was observed. All components contained into the single bicarbonate amino acid-based solution remained practicaly unchanged as the difference between monthly measurements did not exceed ⁇ 1.3%.
  • the pH of the solution ranged withing its initial values (7.25 -7.45).
  • the non sterilized solution of HD even exposed on air preserves its initial pH (7.25-7.45) for more than 8 hr. Apparent formation of insoluble neutral calcium and magnesium carbonate were not observed.
  • Bicarbonate dialysate prepared on-line is rapidly deteriorated during the HD session, and the insoluble calcium and magnesium carbonate deposition reappear on the wall of flow path tubes.
  • Two groups of six rabbits each received i.p. 40 mL/ Kg of either single bicarbonate amino acid-based solution (osmolarity 369 mOsm) and a currently used lactate solution, containing 25 g/L of glucose (osmolarity 408 mOsm), respectively.
  • the animals were sacrificed and the peritoneal fluid was collected, according to a technique reported elsewhere (6). The fluid was measured and net ultrafiltration was calculated as the difference between the infused and drained volume.
  • the mean value of net ultrafiltration was appoximately 25% greater in rabbits received single bicarbonate amino acid-based solution than that with lactate solution (59 ⁇ 2.66 vs 48 ⁇ 2.5, p ⁇ 0.05), although the osmolarity of the first solution was only 369 mOsm and the average mw of amino acids 154.2 against the second solution with an osmolity 408 mOsm and a mw of glucose 180.
  • this increased ultrafiltration may be attributed to either the constant normal pH of the single bicarbonate amino acid-based solution, the presence of amino acids, the absence of glucose and its antioxidant property of PD single bicarbonate solution. Other factors may contribute to increased ultrafiltration.
  • Single bicarbonate HD dialysate was used for a 3-month period in a volunteer patient undergoing regular chronic HD with bicarbonate dialysate prepared on-line for 3 yrs. Biochemical values were compared with those of the last 3- month period. Patient served as his own control. The patient tolerated the single bicarbonate dialysate well, as he did previously with the bicarbonate dialysate prepared on-line.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Inorganic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
EP01600017A 2000-06-28 2001-06-14 Solutions stables pour la dialyse péritonéale et la hémodialyse conténant du bicarbonate et des acides aminés Withdrawn EP1166787A3 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GR20000100214A GR1003567B (el) 2000-06-28 2000-06-28 Νεωτερα ενιαια και σταθερα αμινοξεων-διττανθρακικων πλεονεκτικα διαλυματα για την περιτοναικη καθαρση και αιμοκαθαρση.
GR2000100214 2000-06-28

Publications (2)

Publication Number Publication Date
EP1166787A2 true EP1166787A2 (fr) 2002-01-02
EP1166787A3 EP1166787A3 (fr) 2003-05-14

Family

ID=10944309

Family Applications (1)

Application Number Title Priority Date Filing Date
EP01600017A Withdrawn EP1166787A3 (fr) 2000-06-28 2001-06-14 Solutions stables pour la dialyse péritonéale et la hémodialyse conténant du bicarbonate et des acides aminés

Country Status (2)

Country Link
EP (1) EP1166787A3 (fr)
GR (1) GR1003567B (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7122210B2 (en) 2002-01-11 2006-10-17 Baxter International Inc. Bicarbonate-based solutions for dialysis therapies
EP1889635A1 (fr) * 2006-06-08 2008-02-20 Unipharm AD Concentrés d'hémodialyse
WO2008106702A1 (fr) * 2007-03-02 2008-09-12 Zytoprotec Gmbh Liquide de dialyse péritonéale à base d'hydrate de carbone, comprenant un résidu de glutamine
EP1977773A1 (fr) * 2006-01-24 2008-10-08 Ajinomoto Co., Inc. Agent d amélioration pour maladie d accumulation d aluminium
US7445801B2 (en) 2002-06-07 2008-11-04 Baxter International Inc. Stable bicarbonate-based solution in a single container

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992011046A1 (fr) * 1990-12-18 1992-07-09 The Board Of Regents Of The University Of Washington Systeme de production de dialysat a l'aide de pastilles de dialysat
EP0437274B1 (fr) * 1990-01-12 1994-05-18 Bartz, Volker Solution pour l'infusion et la dialyse contenant du bicarbonate et du calcium
WO2000023086A2 (fr) * 1998-10-20 2000-04-27 Advanced Renal Technologies Compositions tamponnees de dialyse

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3619921B2 (ja) * 1996-09-13 2005-02-16 富田製薬株式会社 重炭酸固形透析用剤

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0437274B1 (fr) * 1990-01-12 1994-05-18 Bartz, Volker Solution pour l'infusion et la dialyse contenant du bicarbonate et du calcium
WO1992011046A1 (fr) * 1990-12-18 1992-07-09 The Board Of Regents Of The University Of Washington Systeme de production de dialysat a l'aide de pastilles de dialysat
WO2000023086A2 (fr) * 1998-10-20 2000-04-27 Advanced Renal Technologies Compositions tamponnees de dialyse

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Section Ch, Week 199824 Derwent Publications Ltd., London, GB; Class B05, AN 1998-267011 XP002161001 & JP 10 087478 A (TOMITA SEIYAKU KK), 7 April 1998 (1998-04-07) *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7122210B2 (en) 2002-01-11 2006-10-17 Baxter International Inc. Bicarbonate-based solutions for dialysis therapies
US7445801B2 (en) 2002-06-07 2008-11-04 Baxter International Inc. Stable bicarbonate-based solution in a single container
EP1977773A1 (fr) * 2006-01-24 2008-10-08 Ajinomoto Co., Inc. Agent d amélioration pour maladie d accumulation d aluminium
EP1977773A4 (fr) * 2006-01-24 2012-08-22 Ajinomoto Kk Agent d amélioration pour maladie d accumulation d aluminium
EP1889635A1 (fr) * 2006-06-08 2008-02-20 Unipharm AD Concentrés d'hémodialyse
WO2008106702A1 (fr) * 2007-03-02 2008-09-12 Zytoprotec Gmbh Liquide de dialyse péritonéale à base d'hydrate de carbone, comprenant un résidu de glutamine
US9931369B2 (en) 2007-03-02 2018-04-03 Zytoprotec Gmbh Carbohydrate-based peritoneal dialysis fluid comprising glutamine residue
US11534475B2 (en) 2007-03-02 2022-12-27 Zytoprotec Gmbh Carbohydrate-based peritoneal dialysis fluid comprising glutamine residue

Also Published As

Publication number Publication date
GR1003567B (el) 2001-04-10
EP1166787A3 (fr) 2003-05-14

Similar Documents

Publication Publication Date Title
AU2002356899B2 (en) Bicarbonate-based solutions for dialysis therapies
US4357343A (en) Nutritional composition for management of renal failure
ES2535867T3 (es) Composición precursora de diálisis
US4434160A (en) Nutrient solution for complete parenteral feeding and for increased energy production
US20060128658A1 (en) Biocompatible dialysis fluids containing icodextrins
Mortelmans et al. Intradialytic parenteral nutrition in malnourished hemodialysis patients: a prospective long‐term study
CA2156733A1 (fr) Solutions de dialyse peritoneale contenant des maltodextrines et des acides amines
Fürst Amino acid metabolism in uremia.
US7857977B2 (en) Packaging of ferric pyrophosphate for dialysis
NZ259242A (en) Nutritional supplement containing amino acids for treating peritoneal dialysis patients
WO1987003806A1 (fr) Therapie de nutrition parenterale avec acides amines
Yatzidis A new stable bicarbonate dialysis solution for peritoneal dialysis: preliminary report
Blackburn et al. Criteria for choosing amino acid therapy in acute renal failure
CN101340904A (zh) 腹膜透析组合物
Motil et al. Complications of essential amino acid hyperalimentation in children with acute renal failure
Cano et al. Branched-chain amino acids: metabolism, physiological function, and application
EP1166787A2 (fr) Solutions stables pour la dialyse péritonéale et la hémodialyse conténant du bicarbonate et des acides aminés
JP2007056013A (ja) 透析用補充液
Oh et al. What unique acid-base considerations exist in dialysis patients?
JP5847712B2 (ja) クレアチン化合物の投与による透析患者の細胞保護
JP6425661B2 (ja) 透析組成物
Shoveller et al. N‐acetylcysteine is a highly available precursor for cysteine in the neonatal piglet receiving parenteral nutrition
US20060079464A1 (en) Peritoneal dialysate containing taurine
JPH1171273A (ja) 腹膜透析液
CA2997328A1 (fr) Formulations solides de pyrophosphate ferrique soluble, kits, et methodes d'utilisation de ceux-ci

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

AX Request for extension of the european patent

Free format text: AL;LT;LV;MK;RO;SI

17P Request for examination filed

Effective date: 20020123

PUAL Search report despatched

Free format text: ORIGINAL CODE: 0009013

AK Designated contracting states

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO SI

RIC1 Information provided on ipc code assigned before grant

Ipc: 7A 61K 31:19 J

Ipc: 7A 61K 31:195 J

Ipc: 7A 61K 31:405 J

Ipc: 7A 61K 31:415 J

Ipc: 7A 61K 33:00 J

Ipc: 7A 61K 33/14 J

Ipc: 7A 61K 33/14 A

AKX Designation fees paid

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20050104